DE2309367A1 - 1,4-DIHYDRO-4-H-ISOCHINOLINE DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION - Google Patents

Description

FARBWERKE HOECHST AG formerly Master Lucius & Brüning 2309367 File number: hoe 73 / F 06k

Date:! February 15, 1973 Dr. D / stl

i: fl5.

Ι, ή-Dihydro-iJ-H-isoquinoline derivatives and processes for their Manufacture "

The invention relates to l, i | -dihydro-2H-isoquinoline derivatives of the general formula I.

R is a straight or branched alkyl chain with 1 to 6 Carbon atoms, or a phenyl ring, or can also be hydrogen, if at the same time X represents a sulfur atom, 2

R is hydrogen, or

2 1

R with R and the carbon atom in the ^ -position is a carbocyclic

Can form 5- or 6-ring,

3 h c

R, R, R are identical or different and are hydrogen, halogen

or represent the nitro group and

X represents an oxygen or sulfur atom.

In particular, the invention includes compounds in the Ί-position carry an alkyl radical with 1 or 2 carbon atoms and the Phenyl ring substituted in the 1-position with 1 or 2 halogen atoms where Cl is particularly preferred and these substituents are preferred are in the ortho or para position.

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The invention also relates to a process for the production and pharmaceutical preparations of these compounds.

The process for the preparation of the compounds according to the invention is characterized in that

a) Compounds of the formula II

II

Y denotes a -CN or -CONHp group with an aldehyde of Formula III

CHO

III to compounds of the formula I.

wherein X is oxygen, converts, b) compounds of the formula IV

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IV

hydrogenated to compounds of the formula I (X = 0),

c) Oximes of the formula V

rearranged according to Beckmann to compounds of formula I (X = 0),

d) compounds of the formula VI

VI

R-

with ammonia or its salts to form compounds of the formula I (X = 0) converts,

e) d-hydroxyacetic acid amides of the formula VII

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VII

cyclized to compounds of the formula I (X = 0),

f) amino acid derivatives of the formula VIII

VIII

wherein X is a carboxylic acid residue or a derivative thereof, or hydroxycarboxamides of the formula IX

IX

cyclized to compounds of formula I (X = 0)

g) metal organyls of the formula X

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R ¹ R ² UZ

wherein U is oxygen, sulfur or nitrogen, Z is alkyl or aryl
and Me is a monovalent metal, preferably lithium,
cyclized to compounds of the formula I (X = 0),

h) Benzylidenebisphenyl acetic acid amides of the formula XI

XI
optionally in the presence of aldehydes of the formula III

, CHO III

converts to compounds of the formula I (X = 0),

i) in compounds of the formula I in which R and / or R is hydrogen

1 2

means, subsequently introduces the substituents R and / or R,

and in the reaction products, if appropriate, replacing the oxygen with sulfur in a manner known per se.

The benzyl cyanides of the general formula II (Y = CN) can
for example by alkylating the corresponding benzyl cyanides

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with an alkyl halide in the presence of sodium amide in the indifferent solvent, for example according to the in Liebigs Annalen, Vol. 561 (19 * 19), pages 52 ff or according to the in J. Am. Chem. Soc. 6J3, (19 ¹ Jo), page 126.

The benzyl cyanides obtained in this way are in the presence of acids Catalysts with or without a solvent with an aldehyde (III) brought to reaction. Mineral acids such as sulfuric acid, hydrochloric acid and phosphoric acid are particularly suitable as catalysts, Lewis acids such as boron trifluoride and aluminum chloride, as well as phosphorus oxychloride. Benzene, for example, can be used as solvents, Toluene, carbon tetrachloride or trichlorethylene in embossing.

The easiest way to do this is to use a procedure that is described in Acta Chim. Acad. May be. Hung. £ 0, page 177 (1969) is given.

One proceeds in such a way that the two reactants are dissolved in phosphoric acid, whose content of phosphorus pentoxide can vary between that of 85% phosphoric acid and that of polyphosphic acid Reaction brings. The process is carried out at temperatures of 50 to 150 ° C., a temperature of 90 to 110 ° C. being preferred. The preferred phosphoric acid for the reaction can be prepared most simply by adding 30 to 70 ml of 85% phosphoric acid mixed with 30 to 70 g of phosphorus pentoxide. The most suitable mixing ratio for the reaction is A ml 85% Phosphoric acid and A g phosphorus pentoxide.

The reaction with phenylacetic acid amides is also carried out in the same way of the formula II (Y = -CO-NH-) most favorable.

The starting compounds IV, which are used according to process b) are obtained, for example, by the method described in J. Heterocyclic Chem. 1_, (197O), page 615 by Compounds of the formula XII of the reaction sequence given there undergoes.

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XII

• CH, OH

O CH ₃ OHZHCl

IV

By reaction with optionally substituted phenyl Grignard reagent, the hydroxy compound XIII is obtained from XII, which is reacted with methanol / hydrochloric acid to form the methyl ether XIV. After splitting off methanol, IV is obtained.

The reduction of IV to I (X = 0) is expediently carried out with metal hydrides such as, for example, sodium borohydride.

Oximes of the formula V are obtained, for example, in accordance with the information in J. Chem. Soc. (C), p. 2245 (1970).

This is based on suitably substituted indan-2-ones XV , R * ·· * ' ^fi> have the meaning already given, and these are added to the.

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XV

Oximes V around. After Beckmann rearrangement, the desired compounds of the formula I (X = 0) are obtained.

The rearrangement is expediently carried out under acidic conditions or, in the case of substituted oximes, under alkaline conditions.

Compounds of the formula VI are obtained, for example, by condensation of phenylacetic acid esters with aromatic aldehydes. These can be reacted with ammonia or its salts to give compounds of the formula I (X = 0). * The terms specified in US Patent 3 Ί80 63 ¹ while you follow appropriate.

HO

COOR

VI

In the implementation according to process e) one follows expediently in Bull. Soc. Chim. France (1966), page 556 or in Khim. Qeterotsikl. Soedin (1966), page 73 ^ specified conditions.

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Suitable amino acid derivatives of the formula VIII also cyclize Water-releasing agents, e.g. acetic anhydride, smoothly Compounds of the formula I (Yakugaku Zasshi 79, 1578 (1959)).

Or you start from hydroxycarboxamides IX, which also under these conditions with elimination of water to the!, M-dihydro-2H-isoquinolin-3-ones cyclize.

In the preparation of the process products according to process g), derivatives of isocyanic acid, for example urethanes, are preferably used

of formula XVI

XVI

from which, for example, with n-butyllithium to the metal organyls of formula X (Me = Li, U = 0, Z = alkyl) are reacted. The cyclization to I is expediently carried out at elevated temperatures in inert solvents.

Since U-Z is split off during the cyclization and thus has no influence on the constitution of the end product, the The meaning of Z can vary within wide limits.

The compounds of the general formula (I) (X = 0) can be obtained from BenzylidenbisphPiylessigsäureamiden XI both in the presence of an aldehyde (III) and without the addition of aldehyde, by acid catalysis, both with a solvent such as benzene, halogenated hydrocarbons or a Alcohol, as well as without a solvent, and polyphosphoric acid or other mineral acids such as hydrochloric acid or sulfuric acid, or Lewis acids such as BF ,, or other acidic catalysts such as POCl ,, can be used.

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In the simplest case one adheres to the Acta. Chim. Acad. May be. Hung 6C), (1969)> Page 177 specified conditions.

The starting compounds XI are obtained by a process known per se, such as, for example, in Chem. Ber. 2 (5, (1893), page 1924 or Liebigs Ann. Chem. 154 , pages 74 and 76 (1870).

1 2

The subsequent introduction of the substituents R and / or R into the isoquinoline structure is carried out by known methods, e.g.

1 2
the substituents R and R in (XVII) can be introduced by stepwise alkylation , it being irrelevant whether with R first

ρ
or R is substituted.

(XVII)

Reactions known per se are used to convert the compounds of the formula I (X = 0) into the corresponding sulfur derivatives of the formula I. The reaction with PhS ₁ in pyridine or toluene with or without the addition of an acid-binding agent such as CaO is particularly suitable, or the procedure is that I (X = 0) is mixed with PCl ₁ . is reacted in pyridine, benzene or toluene to form the imide chloride which, with HS or a thiourea, optionally after hydrolysis of the isothiuronium salt formed as an intermediate, gives compounds of the formula I (X = S).

In the ^ -position unsubstituted l-phenyl-l, ¹ * -dihydro-2H-isoquinolin- 3-ones are without information on a pharmacological effect in Acad. May be. Hung 60, (1969), p. 177. Further l-alkyl-l, ⁱ »-dihydro-2H-isoquinlin-3-ones unsubstituted in the ^ -position are given in US process patent 3,480,634.

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l-Phenyl-l, ¹ l-dihydro-2H-isoquinolin-3-ones or thiones, which are substituted in the ^ -position with an alkyl or phenyl radical, are new compounds.

As compounds according to the invention, in addition to those in the examples The following are preferably produced:

l- (t | -Chlor-3-nitrophenyl) ^-1 * -methyl-l, ¹ l-dihydro-2H-isoquinlin-3-one l- (1-chloro-3-nitrophenyl) -il-ethyl-l, i | -dihydro-2H-isoquinolin-3-one l- (5-chloro-2-nitrophenyl) -il-ethyl-l, H-dihydro-2H-isoquinolin-3-one l- (2-chloro-5- nitrophenyl) -i | -ethyl-l, M-dihydro-2H-isoquinolin-3-one l- (2-chloro-6-nitrophenyl) - '4-ethyl-l, ¹ l-dihydro-2H-isoquinoline-3 -on

l- (H-Pluorphenyl) - '4-ethyl-l, ¹ l-dihydro-2H-isoquinoline-3-one l- (3-Pluorphenyl) - ⁱ l-ethyl-l, ¹ l-dihydro-2H-isoquinoline -3-one l- (2-Pluorphenyl) - ¹ <-ethyl-l, ¹ l-dihydro-2H-isoquinoline-3-one l- (H-bromophenyl) - ¹ i-ethyl-l, ¹ * -dihydro -2H-i3xhinolin-3-one l- (3-bromophenyl) - ¹ l-ethyl-l, ¹ l-dihydro-2H-isoquinolin-3-one 1- (2-bromopheny I) - lJ-ä thy 1- 1, M-dihydro-2H-isoquinoli n-3-one

l- (M-fluorine-2-nitrophenyl) ^-1 * -ethyl-l, ¹ l-dihydro-2H-isoquinolin-3-one l- (2, ¹ »-Dinitrophenyl) - ¹ l-ethyl-l _> ^J 4-dihydro-2H-isoquinolin-3-one l- (2,6-dinitrophenyl) ^-1 l-ethyl-l _> ⁱ l-dihydro-2H-isoquinolin-3-one l- (4-chloro-3-nitrophenyl ) - ¹ <-inethyl-r, ⁱ 4-dihydro-2H-isoquinoline-3-thione l- (M-chloro-3-nitrophenyl) - ^J l-ethyl-l, il-dihydro-2H-isoquinoline-3- thione 1- (5-chloro-2-nitrophenyl) -i | -ethyl-l, i | -dihydro-2H-isoquinoline-3-thione 1- (2-chloro-5-nitrophenyl) ^-1 <-ethyl-l _> ⁱ l-dihydro-2H-isoquinoline-3-thione l- (2-chloro-6-nitrophenyl) - ^ - ethy 1-1, ^ -dihydro-2H-isoquinoline-3-thione l- (l »-Pluorophenyl ) -M-ethyl-l, i | -dihydro-2H-isoquinoline-3-thione 1- (3-pluophenyl) -i | -ethyl-1,4-dihydro-2H-isoquinoline-3-thione 1- (2 -Pluorpheny 1) -4-ethy 1-1, ll-dihydro- 2H-isoquinoline- 3-thione

1- (l | -Brompheny 1) -4-ethy 1-1,4-dihydro- 2H-isoquinoline- 3-thione 1- (3-bromophenyl) -1-ethyl-l, ⁱ l-dihydro-2H -isoc'iinolin-3-thione 1- (2-bromopheny D-1-ethy 1-1,4-dihydro-2H-isoquinolin-3-thione

1- (i »-Pluoro-2-nitrophenyl) -i4-ethyl-l, i» -dihydro-2H-isoquinoline-3-thione 1- (2,4-dinitrophenyl) -4-ethyl-l, ii-dihydro -2H-isoquinoline-3-thione 1- (2,6-dinitrophenyl) -il-ethyl-1- _> l | -dihydro-2H-isoquinoline-3-thione

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The compounds of the invention have valuable therapeutic properties Properties. So they lower serum lipids and can therefore be used to Therapy of primary hyperlipidemias and certain secondary hyperlipidemias, such as in diabetes, with the beneficial effect on the diabetic metabolic solution also manifests itself in a hypoglycemic activity of some of these compounds.

Since an increased blood fat content is the most important risk factor for the development of coronary heart disease and whole generally increased serum lipid values are significant risk factors for the development of arteriosclerotic symptoms, including others Localization, not only in the area of the coronary vessels, is therefore due to the lowering of elevated serum lipids for prophylaxis and the therapy of arteriosclerosis, especially in the area of the coronary arteries, is of exceptional importance. After this the substances described in more detail above can lower normal and elevated serum lipids in animals, they are useful in treatment and prophylaxis of human and animal arteriosclerotic diseases, particularly useful in the area of the coronary vessels, but also in other vascular areas.

The hypolipidemic activity of the listed compounds could can be shown in the following test arrangements, among others:

1. Male rat with normal serum lipid content. The values given in Table 1 represent the changes in the serum concentrations of certain lipid classes after an eight-day treatment in the various daily dosages listed there. The application was carried out orally with a gavage. As a rule, blood was taken before and after the treatment and the concentration of cholesterol in the serum was determined using the Lauber and Richterich method and the triglycerides using the Eggstein and Kreutz method. In the examples given in the tables below, the serum lipid changes that have occurred as a result of treatment with the substances are defined as follows:

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a) the percentage changes in the post-value of the treated group, based on the pre-value of the treated group, the pre-value being set at 100 % and

b) the change in the post-value of the treated group in relation to the post-value of an accompanying untreated control group (placebo group), the placebo group being set at 100 % . The value before a dash represents the percentage change compared to the initial value, the value after a dash represents the percentage change in the preparation group in relation to the placebo group.

2. The carbohydrate- induced hypertriglyceridemia of male rats caused by the administration of pructose. It is greatly reduced by a three-day oral pretreatment with the substances listed compared to a placebo group (Table 2).

The beneficial effect of the compounds of the formula I on the diabetic substance disorder, especially obese and obese people, is not based solely on normalization of the disturbed lipid metabolism, i.e. on the antihyperlipidemic Effect, but also on an effect on the carbohydrate metabolism.

The blood sugar lowering effect was determined as follows:

1. The change in the serum sugar of normal rats that were starved for 20 hours after eight days of treatment with the listed compounds compared to the placebo group. The serum sugar was determined with the autoanalyzer (Table 3).

2. On the influence of blood sugar on (^ rats, which are in found a gluconeogenetic metabolic condition; this became hungry for 44 hours and an additional dose of 10 mg / kg Prednisolone i.p. Induced 24 hours before blood draw. the The compounds listed were administered orally once a day using a stomach tube to nine of the preceding blood samples

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Days and an additional three hours before the blood sample is taken. A placebo group was compared. Determination of serum sugar with the autoanalyzer (table Ό. "

3. The change in blood glucose caused by the listed preparations (compared to a placebo group) in cT rats that were exposed to fructose after three days of oral administration of the listed compounds. The blood glucose was determined directly in the hemolysate using the hexokinase method (Table 5)

The metabolically effective properties of the invention Compounds are very surprising since such properties have not yet become known of compounds of a similar structure.

The new compounds can be used either alone or mixed with pharmacologically acceptable carriers. Oral use is preferred. For this purpose, the active compounds are mixed with substances known per se and brought into suitable dosage forms by methods known per se, such as tablets, hard capsules, aqueous or oily suspensions or aqueous or oily solutions. Magnesium carbonate, lactose or corn starch with the addition of other substances such as magnesium stearate can be used as inert carriers. The preparation can take place either as dry or moist granules. Vegetable and animal oils, such as sunflower oil or cod liver oil, are particularly suitable as oily carriers or solvents. A possible single dose is around 3 to 2oo mg / kg / day .

A special application of the new compounds lies in the combination with other active ingredients. In addition to other suitable substances , these include above all:

Antidiabetic drugs . such as glycodiazine, tolbutamide, glibenclamide, phenformin, buformin, metformin or circulatory agents in the broadest sense, but especially coronary dilators such as chromonar or prenylamine and antihypertensive substances such as reserpine, c ^ -Methy1-Dopa or

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Clonidines, other lipid lowering agents or geriatrics, psychopharr.aka, such as chlordiazepoxide, diazeparn or meprobamate and vitanines

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Table 1

% Change after 8 oral applications to the norraolipidemic o "rat with mg / kg / day

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Verb. Off
example

100

Serum cholesterol

Serum-

Trigyl

ceride

30th

Serum-

Cholesterol

sterol

Serurn

Trigly

ceride

10

Serum cholesterol

Serum-

Trigly

ceride

Serum ChοIe-

sterol

Serum-

Trigly

ceride

σ
co 3 -26 / -54 / -50 -35 / -15 -2U / -2N - 7 / -11 / - 6 - 9 / -32 / -25 co
* \ -24 / -1O. -59 / -2J1 -19 / -20 -29 / -3I cn 5 -41 / -3O -32 / -24 / -15 6th -4O / -35 -32 / -I6 -28 / -30 -34 / -22 -19 / -18 CD
CaJ 7th -35 / -23 -50 / -I9 - 6 / -11 -29 / 8th / -Ik -24 / -21 -63 / -64 9 -16 / -22 / -16 / -33 10 -26 / -64 / -i45 -11 / -29 / -41 / -17 -37 / - ^ iJ 11 -10 / -12 - 6 / -19 12th -25 / -32 / -27 2 -25 / -17 -38 / -49 -21 / - 7 -26 / -3O Clofibrate -1U / -5 ** -3O / -IO -l »2 / -i» 3 -21 / -15 - 8 / - 6 -I5 / -IO ineffective

O CD CO O)

% Change after T a b e Serum- 30th 1 Ie 2 Applications on the Serum- 3 HOE 73 / F 064 Fructose pollution Trigly Serum- and 3 oral Trigly Serum- o * rat with mg / kg / day ceride Cholesterol 10 ceride Cholesterol Verb. Off 100 sterol Serum- -18 sterol example Serum- Serum- Cholesterol -2k -12 Serum- Cholesterol Trigly sterol -32 Trigly- ' sterol ceride -19 ceride 3 -28 5 -26

1 11 CIofibrate

■ 31 ■ 52 ■ 25 ■ 49 • 42

-14

-20

-22

CO Ca) O)

-20

ineffective

ineffective

Table 3

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% Change in serum sugar (autoanalyzer) after 8 oral applications on the <T rat with mg / kg / day

Connections off
example

mg / kg / day

30 mg / kg / day

mg / kg / day

S «

12th

10

Phenformin

/ - 8 / -25

/ -11 / -27 / - k

/ -26

/ -3O ■ 23 / -3O

/ -19 / -27

/ -16
/ -27
/ -4O

O CD CO CD

Table 4

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% Change in serum sugar (autoanalyzer) after 10 oral applications in the starving prednisolone rat with mg / kg / day

• / connections from example 100 mg / kg / day 30 mg / kg / day

- 12

- 30

- 27

- 40

- 33

- 25 N>

- 18 ^

7 ^^ J

09836 2 Phenformin % 5 O
CO
** · 6th 9 12th 10 2

T a b e 1 1 e 5 HOE 73 / F

% Change in blood glucose (hexokinase method) in the fructose-contaminated rat after 3 oral applications compared to the placebo group

_CJ compound from example 100 mg / kg / day 30 mg / kg / day

S 2 ■ - 55

CJ.

1 - 30

Ii - 15

7 -

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Example 1 l, i »-Diphenyl-l, ¹ l-dihydro-2H-i3oquinolin-3-one

50 ml of 85% polyphosphoric acid and 50 g of phosphorus pentoxide are mixed with one another and 19-3 g (0.1 mol) of dipheny / acetonitrile are added at room temperature. The reaction mixture is brought to 80 ° C. and 4.3 g (0.04 mol) of benzaldehyde are added. The mixture is now ^{heated to 100 °} C. for one hour and then another 4.3 g (0.04 mol) of benzaldehyde are added. After a further hour at 100 ° C., the mixture is poured into 1 l of water and made with cone. Ammonia to pH - 10, sucks the crystal and crystallized from Xthanol order.
F .: 178 ° C

Example 2

1- (4-Chlorophenyl) -4-spiro- (1'-cyclopentane) -1, 4-dihydro-2H-isoquinolin-3-one

0.1 mol of 1-cyano-1-phenyl-cyclopentane are given as under 1 reacted with 0.09 mol of 4-chlorobenzaldehyde.

P .: 163 ° C

Example 3

1- (4-chlorophenyl) -4-ethyl-1,4-dihydro-2H-isoquinoline-3-thione

a) 1- (4-chlorophenyl) -4-ethyl-1,4-dihydro-2H-isoquinolin-3-one

0.1 mol of 1-cyano-1-phenyl-propane are with a total of 0.08 mol Ί-chlorobenzaldehyde implemented as indicated under 1..

P .: 153 ° C.

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b) l-Cl-ChlorphehyD - ^ - ethyl-l, ⁱ 4-dihydro-2H-isoquinoline-3-thione

20 in mole l- (1-chlorophenyl) - ^ - ethyl-li ¹ l-dihydro-2H-isoquinolin-1-one are in a suspension of 8 m MoI phosphorus pentasulfide and 32 Hol calcia m introduced with stirring in 50 ml of toluene and Heated under reflux for 15 hours. The hot toluene solution is poured off from the residue through a filter and the resin is extracted twice with 50 ml of benzene each time. The combined organic solutions are concentrated in vacuo and the remaining oil is recrystallized from ethanol.

P.:
Example 4 1- (i | -Nitrophenyl) -1, 4-dihydro-2H-isoquinoline-3-thione

a) l - ('l-Nitrophenyl) -l, ⁱ l-dihydro-2H-isoquinolin-3-one

0.1 mol of benzyl cyanide and 0.08 mol of 4-nitrobenzaldehyde are reacted analogously to 1..

ί P .: 181 ° C

b) 1- ( ^| l-nitrophenyl) -l _> ⁱ J-dihydro-2H-isoquinoline-3-thione

90 m moles l- ⁽¹ J-nitrophenyl) -l, l ^{i-dihydro-2H-isoquinoline-3-one} are dissolved in 35 ml of pyridine and kO m mole of phosphorus pentasulfide was added with stirring. The solution is refluxed for 4 hours and, after cooling, poured into 00 ml of water. 10% potassium hydroxide solution is used to adjust the pH to 8 to 8.5 and the mixture is subsequently stirred for 4 hours. After suctioning off, it is washed with water, air- dried and recrystallized from ethanol.

P .: 176 ° C

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Example 5 1- (2, '<- dichlorophenyl) -l, ⁱ "-dihydro-2H-isoquinoline-3-thione

a) 1- (2, ¹ I-Di chloropheny I) -1, ¹ I-dihydro-2H-isoquinoline n-3 ~ one

Are reacted 0.1 mol of benzyl cyanide nit 0.08 mole of 2, ¹ I-dichlorobenzaldehyde analog. 1

F .: 188 ° C.

b) 1- (2, Ί-dichlorophenyI) -I, ^ - dihydro-2H-isoquinoline-3-thione

20 m moles of 1- (2, ¹ I-dichlorophenyI) -1,4-dihydro-2H-isoquinolin-3-one are introduced into a suspension of 20 m moles of phosphorus pentachloride in 20 ml of toluene and then refluxed for 3 hours. Then H _? S initiated until the evolution of HCl has ended. The solvent is driven off in vacuo and the residue is recrystallized from ethanol.

F .: 189 ° C.

Example 6

1- (2, ¹ I-Di chloropheny 1) -il-ethy 1-1, ¹ l-dihydro-2H-isoquinolin-3-one

From 0.1 mol of 1-cyano-1-phenyl-propane and 0.08 mol of 2,4-dichlorobenzaldehyde analogous to 1.

F .: li »7 ° C. Example 7

l- (2, ¹ »-Dichlorphenyl) - ¹ -ethyl-l, ¹ l-dihydro-2H-isoquinoline-3-thione

Analogous to 3 b) from l- (2, ¹ l-dichlorophenyl) ^-1 ! -Ethyl-l, ¹ l-dihydro-2H-

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isoquinolin-3-one. F .: 154 to 156 ° C. Example 8

1- (3,4-dichlorophenyl) - ⁱ <-ethyl-l _> M-dihydro-2H-isoquinolin-3-one

Analogously to 1. from 0.1 mol of 1-cyano-1-phenyl-propane and 0.08 mol 3,4-dichlorobenzaldehyde.

F .: 136 ° C. Example 9

1- (3,4-Dichlorophenyl) -4-ethyl-1,4-dihydro-2H-isoquinoline-3-thione

From l-iS ^ -Di 3-on analog 3b)

F .: 170 to 171 ° C

ι Example 10

1 ~ (3> ¹ I-Di ch lorpheny 1) - ^ -is opr opy 1-1,4-dihy dr o-2H-is ochi no Ii n-3-on

0.1 mole of 1-cyano-2-methyl-1-phenyl-propane and 0.08 mole of 3,4-dichlorobenzaldehyde are implemented analogously to 1..

F .: 15 * »to 156 ° c. Example 11 1- (2-Chlorophenyl) -4-phenyl-1,4-dihydro-2H-isoquinolin-3-one

Analogously to 1. from 0.1 mol of diphenylacetonitrile and 0.08 mol of 2-chloro

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benzaldehyde

P .: m8 to 150 ° C.

Example 12

1- (3, ¹ J-Di chlorpheny I) -4-n-buty 1-1,4-dihydro-2H-isoquinolin-3 ~ one

Implementation analogous to 1. from 1-cyano-l-phenyl-pentane and 3 ^ -dichlorobenzaldehyde.

F .: 101 to 103 ° C (n-heptane)

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Claims (9)

Claims R means a straight or branched alkyl chain having 1 to 6 carbon atoms, or a phenyl ring, or can also be hydrogen if simultaneously X is sulfur, R is hydrogen, or 2 1 R with R and the carbon atom in the ^ -position can form a carbocyclic 5- or 6-ring, R, R, R are identical or different and represent hydrogen, halogen or the nitro group and X represents an oxygen or sulfur atom. 2. 1- (2, i »-Dichlorophenyl) -l, i» -dihydro-2H-isquinoline-3-thione 3. l-Cl-chlorophenyl) -4-spiro- (l '-cyclopentano) -l, ⁱ »-dihydro-2H- isoquinolin-3-one 1". 1- (2, ^ - dichlorophenyl) -i | -ethyl-l, i | -dihydro-2H-isoquinolin-3-one 5. 1- (2, M-dichlorophenyl) -4-ethyl-1,4-dihydro-2H-isoquinoline-3-thione 6. Process for the preparation of 1, ^ - dihydro-2H-isoquinolin-3 ~ one or 3-thiones of the general formula I. 409836/1034 HOE 73 / F 064 R is a straight or branched alkyl chain with 1 to Carbon atoms, or a phenyl ring, or can also be hydrogen, if at the same time X represents a sulfur atom, 2
R is hydrogen, or R with R and the carbon atom in ^ -position can form a carbocyclic 5- or 6-ring, R, R, R are identical or different and represent hydrogen, halogen or the nitro group and X is an oxygen or Sulfur atom stands, characterized in that a) compounds of the formula II II Y denotes a -CN or -CONHp group with an aldehyde of Formula III CHO Ill 409836/1034 to compounds of the formula I. HOE 73 / F 064 R ' where X is oxygen, converts, b) compounds of the formula IV IV hydrogenated to compounds of the formula I (X = 0), c) Oximes of the formula V rearranged according to Beckmann to compounds of formula I (X = 0), 409836/1034 - 29 d) compounds of the formula VI HOE 73 / F 064 R- with ammonia or its salts to form compounds of the formula I (X = 0), e) cL-hydroxyacetic acid amides of the formula VII cyclized to compounds of the formula I (X = 0), f) amino acid derivatives of the formula VIII wherein X is a carboxylic acid residue or a derivative thereof, or hydroxycarboxamides of the formula IX 409836/1034 HOE? 3 / F 064 IX cyclized to compounds of formula I (X = 0) g) metal organyls of the formula X R ¹ R ² UZ in which ü is oxygen, sulfur or nitrogen, Z is alkyl or aryl and Me is a monovalent metal, preferably lithium, cyclized to compounds of the formula I (X = 0), h) Benzylidenebisphenyl acetic acid amides of the formula XI 0 R ¹ R Ii \ / H 0 R
ι Ii \ N ^ -CC N
H C Il O R- XI optionally in the presence of aldehydes of the formula III 409836/1034 "^ HOE 73 / F 064 CHO III converts to compounds of the formula I (X = 0), 1 2 i) in compounds of the formula I in which R and / or R is hydrogen 1 2 means, subsequently introduces the substituents R and / or R, and in the reaction products, if appropriate, replacing the oxygen with sulfur in a manner known per se. 7. A process for the production of pharmaceutical preparations having a metabolic effect, characterized in that one Compounds according to claim 1, optionally together with pharmaceutical carriers or stabilizers in one for therapeutic Brings appropriate application form. 8. Pharmaceutical preparations with hypolipidemic and antidiabetic Effect, characterized by a content of a compound according to claim 1. 9. Use of compounds of formula I as hypolipidemics and Antidiabetic drugs. 409836/1034